Iboga

Synthesis of camptothecin (163) is another example[133]. The iboga alkaloid analog 164 has been synthesized smoothly by the intramolecular coupling of iodoindole and unsaturated ester to form an eight-membered ring. Af-Methyl protection of the indole is important for a smooth reaction[134]. An efficient construction of the multifunctionalized skeleton 165 of congeners of FR900482 has been achieved[135]. 

R. monobasiana Stapf. (a false iboga, p. 768). Pharmaeologieal examination of an extract. (Raymond-Hamet. )... 

Iboga ibogaine, 768 Ignatius beans, 553 llligera spp., 319 Imperialine, 732 Indaconitine, 673, 684 Indole alkaloids, 484 Indolizine, 16 Insularine, 362, 370... 

Thus the critical synthetic 1,6-dihydropyridine precursor for the unique isoquinuclidine system of the iboga alkaloids, was generated by reduction of a pyridinium salt with sodium borohydride in base (137-140). Lithium aluminum hydride reduction of phenylisoquinolinium and indole-3-ethylisoquinolinium salts gave enamines, which could be cyclized to the skeletons found in norcoralydine (141) and the yohimbane-type alkaloids (142,143). 

Positively activated olefins have also been condensed with dienamines derived from aldehydes 321,330,347,348) and ketones. Of special interest is the formation of bridged systems from homoannular dienes (229-231) which has been applied to the isoquinuclidine system of the iboga alkaloids (137-140,349). 

The ability of 1,2 (or l,6)-dihydropyridines to undergo a Diels-Alder reaction with dienophiles such as methyl vinyl ketone, methyl acrylate, and acrylonitrile has been utilized in the synthesis of polyfunctional isoquinuclidine as a key intermediate in the synthesis of aspidosperma- and iboga-type alkaloids (66JA3099). 

In China, the bark and leaves are used for the treatment of fractures. The roots are used in Malaysia to recover from childbirth and exhaustion, and a paste of the plant is used to treat orchitis. The plant contains indole alkaloids such as conodurinine, 19 (S) hydroxyconoduramin, 19 (S)-hydroxyervahanine A, and related iboga alkaloid congeners, and like the species mentioned earlier, and in fact the genera Ervatamia, in general, would be worth investigating for serotoninergic activities (17). 

Maisonneuve, I.M., Glick, S.D. Anti-addictive actions of an iboga alkaloid congener a novel mechanism for a novel treatment. Pharmacol. Biochem. Behav. 75 607, 2003. 

Glick S., Kuehne M., Caucci J. et al. Effects of iboga alkaloids on morphine and cocaine selfadministration in rats relationship to tremorigenic effects and to effects on dopamine release in nucleus accumbens and striatum. Brain Res. 657 14, 1994. 

Coronaridine subtype alkaloids are widely spread in Tabernaemontana. The iboga skeleton is particularly susceptible to oxidation at aminomethylenes C-3 and C-5 and at benzylic C-6. Very often, the fundamental compounds are accompanied by the oxidation products at these positions. 

A rare and biogenetically interesting example of the ethyl chain functionalization of the iboga skeleton is represented by 18-hydroxycoronaridine (al-bifloranine) (128, C21H26N203, MP 192-194°C, [a]D -210°) isolated from T. albiflora (28). The base peak in its mass spectrum appeared at m/z 323 (M+--31), and this suggested that a hydroxy group was present at C-18. A detailed H-NMR study of 128 in comparison with 97 and heyneanine (122) was reported and shown in Table IV. 

Iboga alkaloids devoid of the 19-hydroxy group are significantly more stable toward oxidation than are the corresponding hydroxy bases. Abstraction of the hydroxy proton of 7-hydroxyindolenines by bases leads to concomitant carbon migration and formation of pseudoindoxyls. In some cases the rearrangement is better accomplished by warm HC1. The interrelationship among indoles, 7-hydroxyindolenines, and pseudoindoxyls has been exhaustively treated by Cordell (see Ref. 6). 

Extensive biotransformation studies have been conducted with the As-pidosperma alkaloid vindoline, but much less work has been done with monomeric Iboga and dimeric alkaloids from this plant. The long-standing interest in this group of compounds stems from the clinical importance of the dimeric alkaloids vincristine and vinblastine, both of which have been used for more than 2 decades in the treatment of cancer. Few mammalian metabolites of dimeric Catharanthus alkaloids have been characterized. Thus the potential role of alkaloid metabolism in mechanism of action or dose-limiting toxicities remains unknown. The fact that little information existed about the metabolic fate of representative Aspidosperma and Iboga alkaloids and Vinca dimers prompted detailed microbial, mammalian enzymatic, and chemical studies with such compounds as vindoline, cleavamine, catharanthine, and their derivatives. Patterns of metabolism observed with the monomeric alkaloids would be expected to occur with the dimeric compounds. 

Leurosine (75) (Scheme 20) is the most abundant of the dimeric antitumor alkaloids isolated from Catharanthus roseus G. Don. Several species of Strep-tomyces produced a common metabolite of the alkaloid, and S. griseus (UI1158) was incubated with 400 mg of leurosine sulfate to obtain 28 mg of pure metabolite (180). The metabolite was identified as 76 primarily on the basis of its H-NMR spectrum. The mass spectrum indicated that the metabolite contained one oxygen atom more than 75. The H-NMR spectrum contained all of the aromatic proton signals of the vindoline portion of the molecule, and aromatic proton signals for the Iboga portion of the compound occurred as a doublet of doublets... 

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